Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA.
Benaroya Research Institute, Seattle, WA, USA.
Matrix Biol. 2023 Nov;123:34-47. doi: 10.1016/j.matbio.2023.09.003. Epub 2023 Sep 30.
Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low concentrations of HA were present in healthy pancreatic islets. However, HA substantially accumulated in cadaveric islets of T2D patients and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the main HA receptor CD44, preserved glycemic control and insulin concentrations in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserved glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we found that 4-MU increased the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation did not result in β-cell apoptosis. These data indicated a role for HA accumulation in diabetes pathogenesis and suggested that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.
胰岛 β 细胞功能障碍和死亡是 2 型糖尿病（T2D）发病机制的核心。我们发现了炎症细胞外基质聚合物透明质酸（HA）在这种病理生理学中的新作用。健康胰岛中存在低浓度的 HA。然而，HA 在 T2D 患者的尸检胰岛和 db/db 小鼠 T2D 模型的胰岛中大量积累，以响应高血糖。用 4-甲基伞形酮（4-MU）（HA 合成的抑制剂）治疗或敲除主要 HA 受体 CD44，尽管持续体重增加，仍能维持 db/db 小鼠的血糖控制和胰岛素浓度，表明该途径在 T2D 发病机制中起关键作用。4-MU 治疗和 CD44 缺失同样能在其他 β 细胞损伤情况下维持血糖控制，包括链脲佐菌素治疗和胰岛移植。从机制上讲，我们发现 4-MU 增加了凋亡抑制剂 survivin 的表达，survivin 是 CD44 依赖性的下游转录靶标，依赖于 HA/CD44 信号，从而使 caspase 3 激活不会导致 β 细胞凋亡。这些数据表明 HA 积累在糖尿病发病机制中的作用，并表明它可能是改善 T2D 中 β 细胞丢失的可行靶点。这些数据特别令人兴奋，因为 4-MU 已经是一种已批准的药物（也称为 hymecromone），这可以加速这些发现转化为临床研究。
